Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Sensitive skin: correlation with skin surface microrelief appearance

BACKGROUND/PURPOSE: Sensitive skin is a condition associated with reduced tolerance to environmental factors and/or the application of topical products, such as cosmetics. Its pathophysiology has not been fully elucidated and few data are available on its prevalence. The aim of this study was to investigate possible correlation between objective sensitivity and skin surface microrelief. METHODS: During an epidemiological survey conducted for a campaign promoted by International Society of Plastic Dermatology in Italy, 243 adult healthy subjects of both sexes with no evident dermatological disorder but positive to the lactic acid stinging test, were submitted to cyanoacrylate stratum corneum stripping from the volar forearm for the determination of the irregularity of the skin surface microrelief (irregularity skin index (ISI)). RESULTS: A significant correlation was found between intensity of symptoms in stingers and ISI (r(s)=-0.47; P<0.001). CONCLUSION: Sensitive skin is common in the healthy population. ISI can contribute towards the identification of subjects with sensitive skin and the development of more specific skin treatments for this prevalent condition.     

Nucleolin protein expression in cutaneous melanocytic lesions

Background:  Nucleolin is a major nucleolar argyrophilic protein involved in carcinogenesis. There are only few studies on its tissue expression in human cancer and none in melanoma. We aimed at exploring this protein and its prognostic impact in cutaneous melanocytic lesions.
Methods:  We studied 193 cases including benign, dysplastic and malignant melanocytic lesions. Nuclear positivity was evaluated by immunohistochemistry and quantified by automated image analysis.
Results:  Most dysplastic and malignant lesions showed high percentages of cells with abnormal patterns of nuclear positivity (Abn+N) consisting in multiple, irregular, positive dots (ID+) and a coarse, irregularly positive nucleoplasm (CNpl+) or both (ID+CNpl+). The patterns CNpl+ and/or ID+CNpl+ were never observed in benign lesions, in which ID+ were also virtually absent. Abn+N% was significantly lower in dysplastic nevi than in primary melanomas and metastases and in primary melanomas than in metastases (p < 0.05). Furthermore, Abn+N was the second powerful prognostic discriminator, after melanoma thickness, and a significantly lower survival was observed in vertical growth phase melanoma patients showing Abn+N in more than 50% of melanoma cells.
Conclusion:  An altered nuclear nucleolin expression seems to accompany melanoma progression. Further investigation on nucleolin functionality and subcellular trafficking could add information on its altered role in melanoma.     

Beneficial effects of C1 esterase inhibitor in ST-elevation myocardial infarction in patients who underwent surgical reperfusion: a randomised double-blind study.

BACKGROUND: The inflammatory cascade has been hypothesized to be an important mechanism of post-ischaemic myocardial reperfusion injury and several studies demonstrated that C1 esterase inhibitor (C1-INH) is effective in post-ischaemia myocardial protection. Therefore, we aimed to investigate prospectively in a randomised double-blind study the cardioprotective effects of C1-INH in ST segment elevation myocardial infarction (STEMI) in patients who underwent emergent reperfusion with coronary artery bypass grafting (CABG). METHODS: In this study, we enrolled 80 patients affected with STEMI who underwent emergent CABG. Patients were assigned in two groups (C1-INH group: receive 1000 UI of C1-INH; and placebo group: receive a saline solution). The effects of C1-INH on complement inhibition, myocardial cell injury extension and clinical outcome were studied. Haemodynamic data and myocardial function were monitored. C1-INH, C3a, C4a complement activation fragments and cardiac troponin I (cTnI) serum levels were measured before, during and after surgery. RESULTS: Patient characteristics were not different between the two groups. The overall in-hospital mortality rate was 6.2%. No statistical significant difference was observed between the two groups with regard to early mortality (p=0.36). Statistical significant difference between the two groups was showed for cardiopulmonary bypass support (p=0.04), administration of high dose of inotropes drugs (p=0.001), time of intubation (p=0.03), intensive care unit (ICU) stay (p=0.04) and in-hospital stay (p=0.03). A significant improvement in mean arterial pressure (p=0.03), cardiac index (p=0.02) and stroke volume (p=0.03) was showed in C1-INH group versus placebo group. The serum cTnI levels were significantly low in the C1-INH group versus placebo group after reperfusion, during the observation period. Plasma levels of C3a and C4a complement fragments were reduced significantly in C1-INH group. No drugs-related adverse effects were observed. CONCLUSIONS: The inhibition of the classic complement pathway by C1-INH appears to be an effective mean of preserving ischaemic myocardium from reperfusion injury as demonstrated by low serum cTnI levels in C1-INH group. Therefore, the use of C1-INH during CABG as a rescue therapy in STEMI patients is probably an effective treatment to inhibit complement activity and to improve cardiac function and haemodynamic performance without impacting early mortality. Large randomised study should be performed to support our results.     

Microvascular abnormalities in patients with rheumatoid arthritis

Microvascular involvement represents one of the first apparent steps in many autoimmune diseases such as rheumatoid arthritis (RA). Early in the disease, peripheral microangiopathy may be easily recognized and studied by videocapillaroscopy. The aim of this study has been to observe the differences in labial microcirculation between healthy patients and patients suffering from RA. A total of 30 healthy patients and 30 patients suffering from RA were examined. The patients with conditions known to compromise microcirculation, such as diabetes, hypertension, or some pharmacological treatments were not included in the study. All the patients were non-smokers. Labial capillaroscopy was used to investigate the characteristics of microcirculation. Visibility, course, tortuosity, as well as the possible presence of microhemorrhages, the average caliber of the capillary loops and the number of visible capillary loops per square millimeter were evaluated for each patient. The investigation was simple, non-invasive, and repeatable for each patient. In patients suffering from RA, it was possible to observe a reduced caliber of capillaries, as well as greater elongated capillaries, in comparison to controls. This study shows that capillary alterations in patients suffering from RA occur in labial mucosa microcirculation; such evidence could be extremely important in the diagnosis of suspected RA.     

Comparison of glycaemic control over 1 year with pioglitazone or gliclazide in patients with Type 2 diabetes.

AIMS: To compare long-term (1 year) efficacy and safety of pioglitazone and gliclazide in patients with Type 2 diabetes. METHODS: This was a double-blind, multicentre, comparative, parallel group trial in 283 patients with Type 2 diabetes, who were randomized to receive 1-year treatment with pioglitazone 30-45 mg/day or gliclazide 80-320 mg/day. Drug dose was titrated on the basis of self-monitored blood glucose (SMBG) measurements and HbA1c values. The 1-year changes in HbA1c, fasting blood glucose (FBG), insulin, HOMA-S (HOmeostatic Model Assessment) and SMBG were compared. In a subgroup of patients (n = 10), systemic glucose production and utilization were determined by a combination of isotopic (deuterated glucose) and clamp techniques. RESULTS: In both groups, there were similar decreases in HbA1c (pioglitazone: -0.79%; gliclazide: -0.79%) and FBG (pioglitazone: -1.0 mmol/l; gliclazide: -0.7 mmol/l), whereas the slope of the reduction of fasting blood glucose was different between groups (P = 0.004). Insulin levels as well as insulin resistance assessed using HOMA-S decreased significantly only after pioglitazone treatment (-11.94 pmol/l and -1.03, respectively, both P = 0.002 vs. baseline). A significantly greater reduction in systemic glucose production was observed in the pioglitazone group (-2.48 micromol/kg/min, P = 0.042) than in the gliclazide group (-1.02 micromol/kg/min). A few, mild adverse events occurred in both groups. CONCLUSIONS: A comparable decrease in HbA1c and FBG was observed with pioglitazone and gliclazide. However, with pioglitazone there was a continuous decrease in FBG over 1 year, whereas gliclazide failed to maintain a similar trend. This favourable effect of pioglitazone was due to its insulin-sensitizing effect and ability to decrease systemic glucose production.     

Telmisartan and irbesartan therapy in type 2 diabetic patients treated with rosiglitazone: effects on insulin-resistance, leptin and tumor necrosis factor-alpha.

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.     

Acral Malignant Melanoma and Striated Palmoplantar Keratoderma (Brunauer-Fohs-Siemens Syndrome): A Fortuitous Association?

Background. Striated palmoplantar keratoderma or Brunauer-Fohs-Siemens syndrome is a very rare, focal, nonepidermolytic palmoplantar keratoderma with autosomal inheritance. Unlike other palmoplantar keratodermas, no association with visceral or skin cancer has ever been reported.
Objective. We report a case of malignant melanoma arising in the hyperkeratotic lesions on the right heel of a patient with striated palmoplantar keratoderma. The lesion was completely excised; our patient also underwent sentinel lymph node biopsy and then was treated with high-dose interferon adjuvant therapy.
Methods. Sentinel lymph node biopsy incision was made in elliptical fashion, long enough to harvest a full-thickness skin graft to cover the wide local excision defect. The skin graft was defatted by sharp dissection. Several perforations were made in graft and it was secured in place with sutures and bolster dressing.
Results. At follow-up, the grafted skin showed hyperkeratotic changes but no local or systemic signs of the disease was observed.
Conclusion. The association between striated palmoplantar keratoderma and acral melanoma is discussed.